Lissoni P, Messina G, Pelizzoni F, Rovelli F, Brivio F, Monzon A, Crivelli N, Lissoni A, Tassoni S, Sassola A, Pensato S, Di Fede G. The Fascination of Cytokine Immuno- logical Science. J Infectiology. 2020; 3(1): 18-28 Journal of Infectiology Journal of Infectiology Review Article Open Access The Fascination of Cytokine Immunological Science Paolo Lissoni1*, Giusy Messina1, Francesco Pelizzoni2, Franco Rovelli1, Fernando Brivio1, Alejandra Monzon1, Na- dal Crivelli1, Arianna Lissoni1, Simonetta Tassoni3, Andrea Sassola1, Sonja Pensato1, Giuseppe Di Fede1 1Institute of Biological Medicine, Milan, Italy 2Cardiological Surgery Division, Niguarda Hospital, Milan, Italy 3Effata Institute, Lucca, Italy Article Info Abstract Article Notes Today, it is known that all human biological functions are under two Received: April 1, 2020 fundamental regulatory systems, consisting of the endocrine system and the Accepted: April 21, 2020 cytokine network. Moreover, it has been shown that the cytokines released *Correspondence: from the activated immune cells do not influence only immune functions, but Paolo Lissoni, Institute of Biological Medicine, Milan, Italy; also the whole biological system, including the various metabolic activities, Email: [email protected]. the cardiovascular system, and the functionless of the neuroendocrine system itself. Unfortunately, despite the well-demonstrated importance of cytokines © 2020 Lissoni P. This article is distributed under the terms of in maintaining the status of health, from a clinical point of view the routine the Creative Commons Attribution 4.0 International License. evaluation of the cytokine system still remains unconsidered to establish Keywords the status of health, since it is investigated only in severe conditions, such as Cytokines septic shock, disseminated intravascular coagulation and respiratory distress, Cytokine network which have been demonstrated to be due to an abnormal endogenous Inflammation production of inflammatory cytokines, namely IL-6, TNF-alpha, and IL-1 beta. Interleukins This clinical deficiency was depended on several factors, particularly on the complexity of cytokine interactions themselves, but also on the decision to use artificial molecules, such as monoclonal antibodies against the various cytokines, to counteract their eventual abnormally enhanced endogenous production, rather than to investigate the mechanisms responsible for their altered production and to correct eventual alterations. The main reason of the complexity of the cytokine network is related to the fact that the interactions occurring among the different cytokines are often founded on positive feedback mechanisms, then on reciprocal stimulatory actions, while the endocrine system is substantially based on negative feedback circuits. The aim of the present review is to propose a synthetic knowledge regarding the main effects and the source of origin of each single interleukin discovered up to now, to elaborate a first preliminary fundamental physiology of the cytokine network. Introduction As “cytokines”, we define a great group of small proteins produced by the immune cells after their activation, as well as by stromal cells, involved in the modulation of the biological immune-inflammatory response, and which are responsible for the pathogenesis of human systemic diseases. The cytokines more exactly produced by lymphocytes were defined with the term of lymphokines. Finally, cytokines received their interleukin (IL) definition at the second International Lymphokinest Conference in Interlaken (Switzerland) in 1979. Since then, the number of interleukins has grown significantly. At the end of 21 century, the total group of interleukins has reached the number of 30, and kept on increasing more, and at present there are currently 40 interleukins named. Obviously, there are only few studies concerning the biological significance of the last discovered 10 interleukins. Moreover, since the last discovered interleukin in Page 18 of 28 Lissoni P, Messina G, Pelizzoni F, Rovelli F, Brivio F, Monzon A, Crivelli N, Lissoni A, Tassoni S, Sassola A, Pensato S, Di Fede G. The Fascination of Cytokine Journal of Infectiology Immunological Science. J Infectiology. 2020; 3(1): 14-28 1 its complete structure was IL-40 in 2017 , and no other a therapeutic point of view, in vivo it is more easy to act interleukin was discovered during the last two years, we by blocking an eventual exaggerated secretion of some may consider, at least from a synthetic and symbolic point cytokines by the administration of specific monoclonal of view, that the number of interleukins may be 40. Finally, antibodies against the single interleukin, whose endogenous some interleukins have received a great attention by the production has been proven to be abnormally increased in Immunologists, while others have been less investigated, each single pathology, such as the enhanced production3 of since they were considered to play a less importance role IL-6, TNF-alpha and TGF-beta in the 4metastatic cancer and in the human biology. In any case, the classification of IL-17 in the autoimmune diseases . On the contrary, in interleukins themselves is still ambiguous, since there is the presence of an interleukin deficiency, such as that of no clear definition of interleukins with respect to that of IL-2 in the advanced neoplasms, the therapy will consist cytokines. Then, some cytokines provided by important of the administration of the interleukin, whose secretion biological effects are not defined as interleukins, for is abnormally low. Finally, the complexity of interleukin example tumor necrosis factor-alpha (TNF-alpha) and system is furtherly amplified 7by the fact that some8, transforming growth factor-beta (TGF-beta), which are interleukins 6may exist in different isoforms, such as IL-17 respectively characterized by proinflammatory, or by anti- in 6 isoforms , IL-36 in 4 isoforms , and IL-37 in 5 isoforms inflammatory effects. Today, it is known that the human as well as by the fact that some isoforms of interleukin may systemic diseases may be interpreted as the end-result display opposite effects. In vivo, there are two fundamental of an interaction between the action of some exogenous mechanisms to protect against an eventual excessive agents and host biological response. Therefore, the human secretion of some cytokines, consisting5 of the production9, which pathologies could be sub-divided into two major classes, of a soluble receptor, such as for IL-2 , or a binding protein consisting of diseases namely depending on the action (BP) for a specific interleukin, such as that for IL-18 of exogenous agents, including microbes and potential actClassification by reducing itsof freeInterleukins amount in the blood. toxic or cancerogenic agents, and diseases mainly due to host immune-biological response. The human systemic diseases, including cancer, autoimmune pathologies and The interleukins may be classified according to three allergy, would depend at least in part on host biological main principles, consisting of their family of origin, which response, consisting of an exaggerated immune reaction, is related to their chemical structure, their effects on the such as autoimmune and allergic pathologies, or a deficient inflammatory response, by classifying interleukins in two immune response, such as that occurring in the neoplastic main groups, respectively provided by proinflammatory or diseases. The endocrine mechanisms may explain some anti-inflammatory activities, and finally their activity on human pathologies, but the most severe human diseases tumor growth. As far as the origin family, it is possible to would be due to an altered immune function. Moreover, recognize 7 fundamental family of interleukins, as follows: while the endocrine system is regulated by negative 1) IL-1 family: this group includes IL-1 beta (since IL-1 feedback mechanisms, which may be understood on alpha is an intracellular protein), IL-18, IL-33, IL-36, IL-37, the basis of rationale considerations, the biology of the and IL-38; 2) IL-2 family: it contains IL-2 itself, IL-7, IL-15, cytokine network cannot be explained only in relation to and IL-21; 3) IL-4 family: it includes IL-4 and IL-13; 4) IL-6 a logical ratio, since most cytokine secretions are linked by family: it is consisting of IL-6 and IL-31; 5) IL-10 family: reciprocal stimulatory effects based on positive feedback it is constituted by several factors, as follows: IL-10, IL-19, mechanisms, as well as since some cytokines may induce IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29; 6) IL-12 family: the secretion of other cytokines provided by opposite it contains IL-12, IL-23, IL-27, IL-30, IL-35, and IL-39; 7) activities in an attempt to counteract their excessive effects IL-17 family: it is characterized by the 6 different isoforms on the biology of the living organisms. Therefore, we need of IL-17 itself. Finally, other interleukins are not classifiable a different mental approach with respect to the simple in a specific family of interleukins, including IL-3, IL-5, IL- mechanic logical ratio, also founded on symbolic archetypic cytokines9, IL-8, IL-11,1 IL-16, IL-25, IL-31, IL-32, IL-34, and IL-40. dynamics. In addition, because of the complex interactions The IL-12 family is unique in having the only heterodimeric among the different interleukins, as well as because the in, . On the other side, as far as the relation with vivo existence of a physiological neuroendocrine regulation2 their effect on the inflammatory status, interleukins may be of the cytokine network and interleukin secretion subdivided into proinflammatory and anti-inflammatory cytokine effects observed in vitro may be different from interleukins. The group of the major proinflammatory those occurring in vivo, and this difference may represent interleukins includes IL-1 beta, IL-2, IL-6, IL-8, IL-12,IL-14, a limiting factor to understand the real impact of the single IL-15, IL-17, IL-18, IL-20, IL-21, IL-22, IL-23, IL-24, IL-26, interleukin in the pathogenesis of human diseases, as well IL-25, IL-28, IL-31, IL-32, IL-35, IL-36, and IL-38.